Project Summary There is growing evidence that myelin, the insulating sheath enveloping axons and enabling rapid information transmission throughout the mammalian brain, may undergo dynamic changes throughout the course of adult life. These changes may be adaptive, and may play an underappreciated role in normal processes of learning and memory. Currently, the mechanisms underlying adaptive myelination are unclear. Intriguingly, the proliferation rate of oligodendrocyte precursor cells (OPCs), the resident stem cells in the brain that differentiate to form myelinating oligodendrocytes, in mice is regulated by neuronal activity, suggesting that communication between neurons and OPCs may mediate adaptive myelin change. A leading candidate for the mode of this communication is neuron-OPC synaptic communication, which has been described in rodents but whose role remains unclear. We have recently found that neuroligin 3 ? a key regulator of neuronal synaptic function ? is highly expressed in OPCs. In this proposal, we intend to shed light on how neuroligin 3 may contribute to adaptive myelination. Understanding mechanisms behind neural activity-induced OPC proliferation is of critical importance in human disease as well, given that many human neural cancers are thought to derive from oligodendrocyte-lineage cells and that selective oligodendrocyte depletion is a hallmark of a range of white matter diseases. In our first aim, we will assess whether neuroligin 3 expression in OPCs is required for myelination. This will be the first cell-specific investigation of the role of a synaptic regulatory protein in white matter development in vivo. In our second aim, we will examine whether deletion of neuroligin 3 in OPCs impacts neuron-OPC synaptic communication, the first study of synaptic regulation at neuron-OPC synapses. In our final aim, we will employ optogenetics ? a technology enabling activation of genetically-defined ensembles of neurons in freely behaving animals ? to determine whether neuroligin 3 is required for neuronal activity-induced adaptive myelination. Taken together, this proposal will enable groundbreaking studies of a leading hypothesized mechanism for neuron-OPC communication that could modulate OPC proliferation and contribute to adaptive myelination. Understanding these mechanisms is likely to prove critical for building our knowledge of how neuron-OPC interactions contribute to learning and memory, development of brain tumors, and pathogenesis and potential therapeutic interventions in white matter disease.